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Introduction: Tubular biomarkers may shed insight into progression of kidney tubulointerstitial pathology complementary to traditional measures of glomerular function and damage., Methods: We examined trajectories of tubular biomarkers in the Diabetes Control and Complications Trial and the Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC Study) of type 1 diabetes (T1D). Biomarkers were measured in a subset of 220 participants across 7 time points over 26 years. Measurements included the following: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor 1 (sTNFR1) in serum or plasma, epidermal growth factor (EGF), monocyte chemoattractant protein-1 (MCP1) in timed urine, and a composite tubular secretion score. We described biomarker trajectories and examined how these were affected by intensive glucose-lowering therapy and glycemia., Results: At baseline, participants had a mean age of 28 years, 45% were women, and 50% were assigned to intensive glucose-lowering therapy. The mean estimated glomerular filtration rate (eGFR) was 125 ml/min per 1.73 m 2 and 90% of participants had a urinary albumin excretion rate (AER) <30 mg/24h. Mean changes in biomarkers over time (percent/decade) were: KIM-1: 27.3% (95% confidence interval [CI]: 21.4-33.5), sTNFR1: 16.9% (14.5-19.3), MCP1: 18.4% (8.9-28.8), EGF: -13.5% (-16.7 to -10.1), EGF-MCP1 ratio: -26.9% (-32.2 to -21.3), and tubular secretion score -0.9% (-1.8 to 0.0), versus -12.0% (CI: -12.9 to -11.1) for eGFR and 10.9% (2.5-20.1) for AER. Intensive versus conventional glucose-lowering therapy was associated with slower increase in sTNFR1 (relative difference in change: 0.94 [0.90-0.98]). Higher HbA1c was associated with faster increases in sTNFR1 (relative difference in change: 1.06 per 1% higher HbA1c [1.05-1.08]) and KIM-1 (1.09 [1.05-1.14])., Conclusion: Among participants with T1D and normal eGFR at baseline, kidney tubular biomarkers changed significantly over long-term follow-up. Hyperglycemia was associated with larger increases in serum or plasma sTNFR1 and KIM-1, when followed-up longitudinally., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Objective: To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals., Research Design and Methods: Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes., Results: In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio [HR] 1.51 [95% CI 1.12, 2.02], P = 0.006), CSME (HR 1.44 [1.10, 1.88], P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 [1.12, 1.96], P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 [95% CI 1.04, 2.06], P = 0.028)., Conclusions: These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals., (© 2023 by the American Diabetes Association.)

Objective: To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels., Methods: Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years., Research Design and Results: The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90)., Conclusions: Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations., (© 2023 by the American Diabetes Association.)

Objective: Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We aimed to determine a simple, risk factor-based screening schedule that optimizes early detection and testing frequency., Research Design and Methods: Urinary albumin excretion measurements from 1,343 participants in the Diabetes Control and Complications Trial and its long-term follow-up were used to create piecewise-exponential incidence models assuming 6-month constant hazards. Likelihood of the onset of moderately or severely elevated albuminuria (confirmed albumin excretion rate AER ≥30 or ≥300 mg/24 h, respectively) and its risk factors were used to identify individualized screening schedules. Time with undetected albuminuria and number of tests were compared with annual screening., Results: The 3-year cumulative incidence of elevated albuminuria following normoalbuminuria at any time during the study was 3.2%, which was strongly associated with higher glycated hemoglobin (HbA1c) and AER. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8% (low risk [0.6% three-year cumulative incidence]), in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9% (high risk [8.9% three-year cumulative incidence]), and in 1 year for all others (average risk [2.4% three-year cumulative incidence]) was associated with 34.9% reduction in time with undetected albuminuria and 20.4% reduction in testing frequency as compared with annual screening. Stratification by categories of HbA1c or AER alone was associated with reductions of lesser magnitude., Conclusions: A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing., Article Highlights: Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We investigated simple screening schedules that optimize early detection and testing frequency. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8%, in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9%, and in 1 year for all others yielded 34.9% reduction in time with undetected albuminuria and 20.4% fewer evaluations compared with annual screening. A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing., (© 2022 by the American Diabetes Association.)

Objective: Individuals with type 1 diabetes mellitus (T1DM) are living to ages when neuropathological changes are increasingly evident. We hypothesized that middle-aged and older adults with long-standing T1DM will show abnormal brain structure in comparison with control subjects without diabetes., Research Design and Methods: MRI was used to compare brain structure among 416 T1DM participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study with that of 99 demographically similar control subjects without diabetes at 26 U.S. and Canadian sites. Assessments included total brain (TBV) (primary outcome), gray matter (GMV), white matter (WMV), ventricle, and white matter hyperintensity (WMH) volumes and total white matter mean fractional anisotropy (FA). Biomedical assessments included HbA1c and lipid levels, blood pressure, and cognitive assessments of memory and psychomotor and mental efficiency (PME). Among EDIC participants, HbA1c, severe hypoglycemia history, and vascular complications were measured longitudinally., Results: Mean age of EDIC participants and control subjects was 60 years. T1DM participants showed significantly smaller TBV (least squares mean ± SE 1,206 ± 1.7 vs. 1,229 ± 3.5 cm3, P < 0.0001), GMV, and WMV and greater ventricle and WMH volumes but no differences in total white matter mean FA versus control subjects. Structural MRI measures in T1DM were equivalent to those of control subjects who were 4-9 years older. Lower PME scores were associated with altered brain structure on all MRI measures in T1DM participants., Conclusions: Middle-aged and older adults with T1DM showed brain volume loss and increased vascular injury in comparison with control subjects without diabetes, equivalent to 4-9 years of brain aging., (© 2022 by the American Diabetes Association.)

Objective: Intensive glycemic control reduces the risk of kidney, retinal, and neurologic complications in type 1 diabetes (T1D), but whether it reduces the risk of lower-extremity complications is unknown. We examined whether former intensive versus conventional glycemic control among Diabetes Control and Complications Trial (DCCT) participants with T1D reduced the long-term risk of diabetic foot ulcers (DFUs) and lower-extremity amputations (LEAs) in the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) study., Research Design and Methods: DCCT participants (n = 1,441) completed 6.5 years on average of intensive versus conventional diabetes treatment, after which 1,408 were enrolled in EDIC and followed annually over 23 years for DFU and LEA occurrences by physical examination. Multivariable Cox proportional hazard regression models estimated associations of DCCT treatment assignment and time-updated exposures with DFU or LEA., Results: Intensive versus conventional glycemic control was associated with a significant risk reduction for all DFUs (hazard ratio 0.77 [95% CI 0.60, 0.97]) and a similar magnitude but nonsignificant risk reduction for first-recorded DFUs (0.78 [0.59, 1.03]) and first LEAs (0.70 [0.36, 1.36]). In adjusted Cox models, clinical neuropathy, lower sural nerve conduction velocity, and cardiovascular autonomic neuropathy were associated with higher DFU risk; estimated glomerular filtration rate <60 mL/min/1.73 m2, albuminuria, and macular edema with higher LEA risk; and any retinopathy and greater time-weighted mean DCCT/EDIC HbA1c with higher risk of both outcomes (P < 0.05)., Conclusions: Early intensive glycemic control decreases long-term DFU risk, the most important antecedent in the causal pathway to LEA., (© 2022 by the American Diabetes Association.)

Objective: Individuals with diabetes have higher resting heart rate compared with those without, which may be predictive of long-term cardiovascular disease (CVD) risk. Using data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, we evaluated whether the beneficial effect of intensive versus conventional diabetes therapy on heart rate persisted, the factors mediating the differences in heart rate between treatment groups, and the effects of heart rate on future CVD risk., Research Design and Methods: Longitudinal changes in heart rate, from annual electrocardiograms over 22 years of EDIC follow-up, were evaluated in 1,402 participants with type 1 diabetes. Linear mixed models were used to assess the effect of DCCT treatment group on mean heart rate over time, and Cox proportional hazards models were used to estimate the effect of heart rate on CVD risk during DCCT/EDIC., Results: At DCCT closeout, 52% of participants were male and mean ± SD age was 33 ± 7 years, diabetes duration 12 ± 5 years, and HbA 1c 7.4 ± 1.2% (intensive) and 9.1 ± 1.6% (conventional). Through EDIC, participants in the intensive group had significantly lower heart rate in comparison with the conventional group. While significant group differences in heart rate were fully attenuated by DCCT/EDIC mean HbA 1c , higher heart rate predicted CVD and major adverse cardiovascular events independent of other risk factors., Conclusions: After 22 years of follow-up, former intensive versus conventional therapy remained significantly associated with lower heart rate, consistent with the long-term beneficial effects of intensive therapy on CVD. DCCT treatment group effects on heart rate were explained by differences in DCCT/EDIC mean HbA 1c ., (© 2021 by the American Diabetes Association.)

Objective: This epidemiological analysis of the pooled Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort describes the equivalence of a 1-percentage point increase in HbA 1c (such as from 7% to 8%) and years of additional age or duration of type 1 diabetes (T1D) relative to the risk of complications., Research Design and Methods: Separate Cox proportional hazards models determined the number of additional years of age and/or duration of T1D that would result in the same increase in risk of microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications and mortality as a 1-percentage point increase in HbA 1c ., Results: The risk of any cardiovascular disease associated with a 1-percentage point increase in HbA 1c was equivalent to the risk associated with 4.3 (95% CI 2.7-5.9) additional years of age or 5.6 (95% CI 2.7-6.5) additional years' duration of T1D. The risk of estimated glomerular filtration rate <60 mL/min/1.73 m 2 and/or end-stage renal disease associated with a 1-percentage point increase in HbA 1c was equivalent to the risk associated with 12.1 (95% CI 8.3-15.9) additional years of age or 18.0 (95% CI 4.3-31.7) additional years' duration of T1D. The proliferative diabetic retinopathy risk associated with a 1-percentage point increase in HbA 1c was equivalent to the risk associated with 6.4 (95% CI 5.3-7.4) additional years' duration of T1D, while for mortality risk, it was equivalent to the risk associated with 12.9 (95% CI 6.6-19.3) additional years of age., Conclusions: Our results help evaluate the impact of glycemia on advanced complications in a way that may be more interpretable to health care providers and individuals with T1D., (© 2020 by the American Diabetes Association.)

Objective: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study has demonstrated the major role of hyperglycemia as a risk factor for clinical cardiovascular outcomes in type 1 diabetes (T1D). We assessed whether and to what extent the effect of glycemia is mediated by other established cardiovascular disease (CVD) risk factors., Research Design and Methods: In the DCCT, 1,441 participants were randomized to receive either intensive or conventional diabetes therapy. The EDIC observational follow-up study enrolled 96% of the surviving DCCT cohort with 94% of the survivors still actively participating after more than 27 years of follow-up. Mediation of the effect of glycemia, as captured by HbA 1c , on the subsequent CVD risk was quantified using the relative change in the CVD risk associated with HbA 1c between models without and with the potential mediator., Results: Adjusted for age, only a few factors (e.g., pulse, triglycerides, albumin excretion rate) explained more than 10% of the effect of glycemia on CVD risk when considered individually. In multivariable models, these traditional risk factors together mediated up to ∼50% of the effect of glycemia on the risk of CVD. However, the association between HbA 1c and the risk of CVD remained highly significant even after adjustment for these risk factors., Conclusions: While HbA 1c is associated with many traditional CVD risk factors, its association with these factors alone cannot explain its effects on risk of CVD. Consequently, aggressive management of traditional nonglycemic CVD risk factors, coupled with aggressive glycemic management, is indicated for individuals with type 1 diabetes., (© 2019 by the American Diabetes Association.)

Objective: To evaluate the prevalence of hearing impairment in participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study and compare with that of a spousal control group without diabetes. Among participants with type 1 diabetes, to evaluate the association of hearing impairment with prior DCCT therapy and overall glycemia., Research Design and Methods: DCCT/EDIC participants ( n = 1,150) and 288 spouses without diabetes were recruited for the DCCT/EDIC Hearing Study. All subjects completed a self-administered questionnaire, medical history, and physical measurements. Audiometry was performed by study-certified personnel; audiograms were assessed centrally. Speech-frequency (pure-tone average [PTA] thresholds at 500, 1,000, 2,000, and 4,000 Hz) and high-frequency impairment (PTA thresholds at 3,000, 4,000, 6,000, and 8,000 Hz) were defined as PTA >25 dB hearing loss. Logistic regression models were adjusted for age and sex., Results: DCCT/EDIC participants and spousal control subjects were similar in age, race, education, smoking, and systolic blood pressure. There were no statistically significant differences between groups in the prevalence or adjusted odds of speech- or high-frequency impairment in either ear. Among participants with type 1 diabetes, for every 10% increase in the time-weighted mean HbA 1c , there was a 32% (95% CI 1.15-1.50) and 19% (95% CI 1.07-1.33) increase in speech- and high-frequency hearing impairment, respectively., Conclusions: We found no significant difference in the prevalence of hearing impairment between the group with type 1 diabetes and the spousal control group. Among those with type 1 diabetes, higher mean HbA 1c over time was associated with hearing impairment., (© 2018 by the American Diabetes Association.)

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.